18F-fluorodeoxy-glucose positron emission tomography marks MYC-overexpressing human basal-like breast cancers.
18F-fluorodeoxy-glucose positron emission tomography marks MYC-overexpressing human basal-like breast cancers.
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DOI：
10.1158/0008-5472.can-10-4633
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发表时间：
2011-08-01
期刊：
影响因子：
11.2
通讯作者：
Mellinghoff IK
中科院分区：
文献类型：
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作者：
Palaskas N;Larson SM;Schultz N;Komisopoulou E;Wong J;Rohle D;Campos C;Yannuzzi N;Osborne JR;Linkov I;Kastenhuber ER;Taschereau R;Plaisier SB;Tran C;Heguy A;Wu H;Sander C;Phelps ME;Brennan C;Port E;Huse JT;Graeber TG;Mellinghoff IK
与正常细胞相比，即使在氧气充足的情况下，癌细胞也会热衷于摄取葡萄糖并将其代谢为乳酸，这一现象被称为华宝效应。静脉注射葡萄糖类似物18F-氟脱氧葡萄糖(18FDG)后，癌细胞葡萄糖代谢的这一根本变化使正电子发射断层扫描(PET)能够特异性地检测到它们。然而，这种有用的成像技术受到这样一个事实的限制，即并不是所有的癌症都热衷于摄取FDG。为了确定18FDG滞留的分子决定因素，我们对人类癌细胞株和原发肿瘤的转录本进行了研究，以寻找与18FDG放射性示踪剂摄取相关的代谢途径。在被询问的95条代谢途径中，糖酵解和几条与糖酵解相关的途径(戊糖-磷酸、碳固定、氨基酰基-tRNA生物合成、叶酸的一个碳库)显示出最大的转录丰富。这一“FDG信号”预测了乳腺癌细胞系中FDG的摄取，并与已建立的“基底样”乳腺癌亚型和MYC诱导的小鼠肿瘤形成的基因表达信号重叠。具有MYC核染色和MYC靶基因高表达的人乳腺癌显示高摄取18FDG-PET(p<；0.005)。在人类乳腺癌基因组数据集中，FDG信号的存在与MYC基因拷贝增加、MYC转录本水平增加和代谢MYC靶基因表达增加类似。总而言之，我们的发现将葡萄糖摄取的临床观察与人类乳腺癌的一个病理和分子亚型联系起来。此外，他们提出了相关的方法来推导其他PET成像探针的放射性示踪剂保留的分子决定因素。
In contrast to normal cells, cancer cells avidly take up glucose and metabolize it to lactate even when oxygen is abundant, a phenomenon referred to as the Warburg effect. This fundamental alteration in glucose metabolism in cancer cells enables their specific detection by Positron Emission Tomography (PET) following intravenous injection of the glucose analogue 18F-fluorodeoxy-glucose (18FDG). However, this useful imaging technique is limited by the fact that not all cancers avidly take up FDG. To identify molecular determinants of 18FDG-retention, we interogated the transcriptomes of human cancer cell lines and primary tumors for metabolic pathways associated with 18FDG radiotracer uptake. From 95 metabolic pathways that were interrogated, the glycolysis and several glycolysis-related pathways (pentose-phosphate, carbon fixation, aminoacyl-tRNA biosynthesis, one-carbon-pool by folate) showed the greatest transcriptional enrichment. This “FDG signature” predicted FDG-uptake in breast cancer cell lines and overlapped with established gene expression signatures for the “basal-like” breast cancer subtype and MYC-induced tumorigenesis in mice. Human breast cancers with nuclear MYC staining and high RNA expression of MYC target genes showed high 18FDG-PET uptake (p < 0.005). Presence of the FDG signature was similarly associated with MYC gene copy gain, increased MYC transcript levels, and elevated expression of metabolic MYC target genes in a human breast cancer genomic dataset. Together, our findings link clinical observations of glucose uptake with a pathologic and molecular subtype of human breast cancer. Further, they suggest related approaches to derive molecular determinants of radiotracer retention for other PET-imaging probes.